Genetic Epidemiology of Metabolic Disorders in African Americans: CRGGH conducted Genome Wide Association Studies (GWAS) in a sample of over 2,000 African Americans to shed light on the clustering of metabolic disorders such hypertension, obesity, insulin resistance, type 2 diabetes (T2D), dyslipidemia and kidney function. The first genome-wide association study in African Americans was conducted by CRGGH in the HUFS using the Affymetrix 6.0 Human SNP Array with over two million genetic markers. Six SNPs reached genome-wide significance for systolic BP in or near the genes PMS1, SLC24A4, YWHA7, IPO7, and CACANA1H. Two of these genes, SLC24A4 (a sodium/potassium/calcium exchanger) and CACNA1H, are potential targets for BP regulation (PLoS Genetics. Jul 2009). Also, we published the first GWAS for serum uric acid in African Americans (BMC Med Genomics. 2011;4:17). Elevated serum uric acid is a known risk factor for hypertension. In addition, we participated in the largest international GWAS consortia for BP (Nature. Oct 6 2011) as well as the CARe African American cohorts for blood pressure (Hum Mol Genet. Jun 1 2011) and renal function (PLoS Genet. Sep 2011). CRGGH contributed to several international T2D consortia, including the ongoing Meta-analysis of T2D in Africa Americans (MEDIA) Consortium, in which the meta-analysis of 17 GWAS for T2D in over 8,000 cases and 16,000 controls has been performed. Investigators at CRGGH are playing leading role in the analysis and interpretation of data. Genetic Epidemiology of Metabolic Disorders in Africans: In over a decade, investigators at CRGGH, Howard University and multiple institutions in Nigeria, Ghana and Kenya worked together to establish a large-scale genetic epidemiology diabetes project entitled the African American Diabetes Mellitus (AADM) study. The AADM study which has enrolled over 6,000 cases of T2D and controls uses the genome-wide association and linkage approaches to search for susceptibility genes for diabetes. The AADM study has been extremely successful with several publications in high impact journals. For example, the AADM study, in collaboration with deCODE Genetics, made significant contribution in 2007 to the global understanding of the genetic basis of diabetes by identify one of the most consistently replicated gene (TCF7L2) for T2D. CRGGH has completed the genotyping of 2,400 Africans with diabetes and controls to conduct the first GWAS in Africans for T2D. Analysis of this unique data is ongoing. The genetic basis of other metabolic traits will also be investigators. CRGGH has completed whole-exome sequencing of 20 African American families with multiple affected persons and 20 West African families with at least 4 affected family members. Data analysis is ongoing. CRGGH investigators are co-applicant, at no cost, of the newly funded project entitled Burden, Spectrum and Etiology of Type 2 Diabetes in sub Saharan Africa. This five-year 3M Wellcome Trust H3Africa Strategic Award will fund a consortium of 16 centers in 9 African countries, the UK, and the US. The consortium will establish a large scale epidemiological and genomic research resource comprising 12,000 T2D cases and 12,000 controls drawn from sub-Saharan Africa to assess the burden and etiology of T2D and its complications. Genetics of dyslipidemia: In contrast to the increased prevalence of hypertension, T2D, and obesity observed with increasing degree of westernization, there is remarkable similarity in the distribution of serum lipid parameters across populations of the African Diaspora. In the US, interethnic differences in serum lipid distributions are consistently observed, with African Americans having a generally healthier lipid profile, characterized by lower TG and higher HDL, than European Americans. These results are found despite differences in lifestyle factors that would be expected to produce a worse lipid profile among AA. This observation, coupled with the relative similarity in distribution of lipids between West Africans and Africa Americans with even greater differences in lifestyle characteristics, suggests that the healthier lipid profile among African Americans has a genetic basis. Research activities at CRGGH are shedding light on these observations. Statistical Approaches and Methods Development: CRGGH investigators are internationally recognized expertise in the analysis of complex traits in admixed African Americans and other African Diaspora populations, as exemplified by a recent invited review on mapping disease-associated variants in admixed populations published in Genome Biology and an American Society of Human Genetics 2010 invited session Complex Disease Genetics Research in Admixed Populations. CRGGH researchers are responsible for considerable advances in the development of analytical tools for admixed populations. We have also developed tools that respond to the changing resources and challenges of the field as a whole: novel approaches for the simultaneous analysis of common and rare variants, approximate and exact tests of Hardy-Weinberg equilibrium using uncertain genotypes, and a test for gene-gene interactions in case-control studies. Pharmacogenomics: We have generated a database of pharmacogenomically-relevant gene variants by mining the 1000 Genomes database and conducting de novo genotyping in the NHGRI Microarray Core using the Affymetrix ADME gene chip in 19 global populations sampled from 5 continents (Africa, North and South America, Europe and Asia) for a total of 1,478 persons. Based on this global data, we showed that the use of general descriptors (white, black, and Asian), groupings that refer to a social construct, is inappropriate in terms of health decisions. In collaboration with CRGGH Special Volunteer Shawneequa Callier, J.D. of George Washington University, we received funding to study physicians assumptions on genetics and race/ethnicity in the treatment of hypertensive AA on Medicare. This study promises insights into how pharmacogenomic knowledge is used in clinical decision-making and how race is used by physicians when prescribing drugs. Genetic Epidemiology of Podoconiosis: Podoconiosis (Podo) is a devastating, stigmatizing, and neglected tropical disease characterized by lymphedema resulting from long-term barefoot exposure to red-clay soil derived from volcanic rock. It is entirely preventable by wearing shoes. Not all exposed persons develop the disease, and we have shown that Podo is highly heritable (h2 63%). So far, research projects conducted by our team have shed light on the clinical staging of Podo; the economic, ethical, and social issues surrounding the implementation of genomic research in resource-poor settings; the use of genetic information to improve primary prevention strategies; and the genetic basis of Podo (NEJM 2011). African Genome Variation Project (AGV): In collaboration with investigators at the Sanger Institute (UK) and institutions across Africa, weve established the AGV project. This project used the Illumina 2.5M chip to genotype 100 individuals from each of 18 ethnic groups from Africa. CRGGH investigators are analyzing generated data with the promise of informing genomic studies in Africa by providing a reference for allelic, haplotype, and LD structure for common variants in populations not covered by HapMap and the 1000 Genomes projects. Societal Implications of Genomic Research: CRGGH pays particular attention to the documentation and description of the non-random pattern of human genetic variation and its link to disease risks in different populations. By engaging in constructive conversations on these issues, we are contributing to the untangling of the complexities of genetic variation within the context of health disparities and group identity (NEJM 2010; BMC Medical Genomics 2009).